Inappropriate activation of the beta-catenin signaling pathway is a major cause of colon cancer, and has also been implicated in the pathogenesis of breast and prostate cancer, chronic lymphocytic leukemia and multiple myeloma. Hence, there is a compelling need for the discovery and development of low molecular pharmacologic antagonists of beta-catenin signaling. Previous experiments from this and other laboratories have shown that some non-steroidal anti-inflammatory drugs (NSAIDs) can block beta-catenin nuclear localization and transcriptional activity, independent of any effect on cyclo-oxygenases (COX). Recent results have suggested that this inhibition is attributable to disruption of a dynamic nuclear complex containing beta-catenin, PPAR-y, RXR, and the pro-apoptotic protein TR3 (Nur77). The dismantling causes degradation of PPAR-y, cytoplasmic relocalization of beta-catenin and RXR, and mitochondrial translocation of TR3. The overall goals of this component of NCDDG program are to exploit the pharmacologic leads and assay systems developed in our preliminary experiments in order to identify high affinity pharmacologic antagonists of beta-catenin signaling, and to validate the specific chemotherapeutic activity of these agents in transgenic models of cancer. The Specific Aims of the project are: [1] to perform a structure activity relationship analysis among known NSAIDs, and novel NSAID congeners lacking COX inhibitory activity, using cell-based assays that measure different properties of the beta-catenin nuclear complex, [2] to complete a similar analysis among a series of xanthine-like bicyclic heterocyclic drugs, reported by others to inhibit beta-catenin activity, [3] the confirm the in vivo activity of the most potent agents in transgenic models of breast and prostate cancer in which beta-catenin activation plays a pathogenic role. When complete, these experiments may lead to the clinical development of new drugs that target one of the most critical biochemical pathways in cancer.